Classic Galactosemia is an inherited metabolic condition caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12) activity. GALT is the second enzyme in the evolutionarily conserved galactose (Leloir) metabolic pathway, and facilitates the simultaneous conversion of uridine diphosphoglucose (UDP-glucose) and galactose-1-phosphate (gal-1-p) to uridine diphosphogalactose (UDP-galactose) and glucose-1-phosphate. Consequently, GALT deficiency leads to the unique accumulation of gal-1-p and deficiency of UDP-galactose in patient cells. If untreated, Classic Galactosemia can result in severe disease in the newborn period, including direct hyperbilirubinemia, quickly progressing to acute liver failure, coagulopathy, coma and death. Ever since most states in the USA included Classic Galactosemia in the newborn screening panel, neonatal morbidity and mortality have decreased considerably. The current mainstay of treatment is the withdrawal of (ga-)lactose from the diet.
However, it has become clear that despite optimal dietary management, chronic complications such as IQ deficits, ataxia, speech dyspraxia, and premature ovarian failure persist, and that gal-1-p remains elevated in patients with Classic Galactosemia. The pathogenic mechanisms for the chronic complications remain uncertain, but several lines of evidence strongly suggested that the chronically elevated gal-1-p is the major contributor to the long-term sequelae of Classic Galactosemia. Firstly, except for cataracts, patients with inherited deficiency of galactokinase (GALK, E.C. 2.7.1.6) (OMIM 230200) do not accumulate gal-1-p, and do not experience the range of complications seen in GALT-deficient patients. Secondly, while a gall-deleted (i.e., GALT-deficient) yeast stops growing upon addition of galactose to the growth medium, a gal7 gal1 double knock-out strain deficient in both GALT and GALK enzyme activities is no longer sensitive to galactose. Thirdly, our laboratory recently demonstrated that galactose challenge to isogenic GALT-deficient (but not GALK-deficient) yeast led to overt manifestation of environmental stress response (ESR). All these studies strongly indicate that gal-1-p is the major, if not sole, culprit for the galactose toxicity observed in GALT-deficient cells.
This raises the question about the origin of gal-1-p, the enzymatic product of galactokinase (GALK) on galactose, in a galactosemic patient who refrains from dairy products. It has been found that galactose moieties converted to gal-1-p can also come from non-dairy sources, e.g. galactose-containing fruits and vegetables amounting to as much as 30 mg/day. However, galactose moieties can also be produced endogenously from UDP-glucose via the UDP-4-galactose epimerase (GALE) reaction, as well as from the natural turnover of glycolipids and glycoproteins. In fact, using isotopic labeling, it was shown that a 50 kg adult male could produce up to 1.2 grams of galactose per day, which is many times of the amount of exogenous galactose potentially present in galactose-restricted diets. Therefore, endogenous synthesis of galactose is likely to undermine the efficacy of dietary management as standard therapy. Since endogenous galactose production is not amenable to dietary manipulation, there is a need for innovative, non-dietary therapy.